Our earlier filed PCT applications WO02/070516 & WO03/020705 claim novel NNRTIs of the formula I
where;R1 is O, S;R2 is an optionally substituted, nitrogen-containing heterocycle, such as pyridyl;R3 is H, C1-C3 alkyl,R4-R7 are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, haloC1-C6 alkyl, C1-C6 alkanoyl, haloC1-C6 alkanoyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkyloxyC1-C6 alkyl, haloC1-C6 alkyloxyC1-C6 alkyl, hydroxyC1-C6 alkyl, aminoC1-C6 alkyl, carboxyC1-C6 alkyl, cyanoC1-C6 alkyl, amino, carboxy, carbamoyl, cyano, halo, hydroxy, keto and the like;X is —(CH2)n-D-(CH2)m— or X is —(CRaRb)c—D is —NR8—, —O—, —S—, —S(═O)— or —S(═O)2—R8 is H, C1-C3 alkylRa and Rb are independently H, C1-C3 alkyl, OH or Ra and Rb together are ═On and m are independently 0 or 1;c is 1, 2 or 3and pharmaceutically acceptable salts and prodrugs thereof.
Example 20 of WO 02/070516 discloses the compound
which is stated to have an ED50 of 7 nM against wild type HIV (HIVIIIB).
Our co-pending, but as of the priority date unpublished PCT application WO 04/021969 discloses compounds generally of the formula I above, but wherein R2 is pyrid-2-yl substituted at the 5 position with a group of the formula —(CHR11)p-E-(CHR11)q—R10 where E is E is —CH2—, —CHOH—, —C═O—, —NR9—, —O—, —S—, —S(═O)2—;
p and q are independently 0, 1 or 2, where p+q≦2;
R10 is a monocyclic ring which is optionally substituted with halo, cyano, morpholinomethyl- or morpholinoketo-; and
R11 is independently H, C1-C3 alkyl, halo substituted C1-C3alkyl or hydroxy.
Although the urea and thiourea NNRTIs disclosed in the above documents are exquisitely active against reverse transcriptase, especially that of HIV-1, the nature of the HIV virus with its extreme lack of replicative fidelity and consequent tendency to rapid resistance development prompts a demand for further antiretroviral agents with enhanced antiviral performance against problematic drug escape mutants, notably at the RT 100, 103 and/or 181 positions.